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ItemStriatal morphology, frontostriatal circuits and functional correlates in neurodegenerative diseaseLooi, Jeffrey Chee Leong ( 2017)This thesis comprises five major sections, based on research work that I have led via an international network of collaborators that I established. The studies in this thesis are targeted at characterising quantitative measures of the structural integrity of recurrent fronto-striato-pallido-thalamo-cortical neural circuits and the relationship of such measures to clinical manifestations of neurodegenerative disease. Section 1 presents the foundational basis of my conceptualisation of quantitative measurement of human brain neuroanatomical structures (shape and volume – morphology), specifically, the striatum, as a means of developing in vivo biomarkers that correlate to clinical intermediate phenotypic manifestations (endophenotypes) of neurodegenerative disease. I describe here the international collaborative research network I established to conduct the research program embodied in this thesis. Section 2 involves the results of studies of the in vivo morphology of the striatum in neurodegenerative diseases in which neuropathology of the striatum has been implicated, comparing relative differences in striatal morphology between disease groups. In Section 3, I extend the work in Section 2 by examining whether quantitative morphology (morphometry) of the striatum correlates to endophenotypic cognitive, emotional, behavioural and motoric manifestations of the specific neurodegenerative diseases. In Section 4, the theoretical underpinning of the conceptualisation of the thalamus as another target for quantitative morphology and correlation to endophenotype, as well as the development of an innovative quantitative manual measurement method for the thalamus, is described. Through the works in Sections 1-4, I had come to conceptualise a subcortical connectome (Section 5): a quantitative mapping of the hubs and spokes of recurrent neuroanatomical circuits, as well as potentially the spaces between the structures underlying and connecting to the cortex. In Section 5, I also describe the development of a further vision for my collaborative research program. Section 1: The first two chapters describe the theory and hypotheses underpinning my research on the quantitative morphometry (measurement of shape and volume) of fronto-striato-pallido-thalamo-cortical (frontostriatal) circuit hubs in neurodegenerative disease. Chapter 1 describes the conceptual background for the study of striatal morphology, a key hub of frontostriatal circuits, as a potential biomarker in neurodegenerative disease. Chapter 2 extends the striatal morphology biomarker model to the frontotemporal dementias towards establishing potential intermediate phenotypes (endophenotypes). Chapter 3 describes the Australian, US, Scandinavian Imaging Exchange (AUSSIE) research network I established to conduct the research program and to expand our knowledge of the role of the subcortical connectome as a potential biomarker in neurodegenerative disease. Section 2: Chapters 4-7 describe the application of the theory and methods outlined in section 1, initially in differentiating between neurodegenerative disease groups that have striatal morphologic change implicated as part of disease progression. Chapters 3 and 4 describe cross-sectional studies of differential striatal morphometry in frontotemporal dementia subtypes and Alzheimer’s disease (AD). Chapter 5 describes the application of striatal morphometry to progressive supranuclear palsy (PSP), whilst Chapter 6 describes cross-sectional studies of differential striatal morphometry in Huntington’s disease (HD), frontotemporal dementia (FTD) and Alzheimer’s disease. Section 3: Chapters 8-10 describe the extension of the striatal morphometric work to investigate functional correlations of morphology with clinical manifestations of the cognitive, emotional and motor circuits subserved by frontostriatal circuits, i.e. towards establishing an endophenotype. Chapters 7 and 8 describe correlations of striatal morphometry with executive dysfunction and gait disturbance in a cohort of persons with age-related white matter change respectively. Chapter 9 describes correlations of striatal morphometry with measures of behavioural change in frontotemporal dementia. Section 4: Chapters 11-12 describe development of methods for further research into another hub in fronto-striatal circuits (Chapter 10). Chapter 10 describes the characterisation of another crucial hub in frontostriatal circuits, the thalamus, and the rationale for further investigation. Chapter 11 describes the development of a method for manual neuroanatomical measurement of the thalamus for quantification of its shape and volume, i.e. morphology, in neurodegenerative disease. Section 5: Chapter 13 describes the conceptualisation of the overarching concept of the subcortical connectome to direct further research extending to other key subcortical structures and spaces in neurodegenerative disease. This thesis describes the development of quantitative measures of the shape and volume of crucial brain neurocircuit hubs (quantified morphology = morphometry) in human neurodegenerative disease that correlate to clinical cognitive, emotional, behavioural and motoric manifestations of disease aimed towards developing endophenotypes.